title: Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial.
abstract: BACKGROUND
  Narcolepsy is characterised by excessive daytime sleepiness (EDS) and cataplexy. Histamine neurons are crucial to maintain wakefulness. We assessed the safety and efficacy of pitolisant (previously called BF2.649), a selective histamine H3 receptor inverse agonist that activates these neurons, in patients with narcolepsy.
  
  
  METHODS
  For this double-blind, randomised, parallel-group controlled trial, we recruited patients with narcolepsy from 32 sleep disorder centres in five European countries. Patients were eligible if they were aged 18 years or older, had not taken psychostimulants for at least 14 days, and had EDS (defined as an Epworth Sleepiness Scale [ESS] score of at least 14). Using a computer-generated randomisation sequence, we randomly allocated patients to receive pitolisant, modafinil, or placebo (1:1:1). Treatment lasted 8 weeks: 3 weeks of flexible dosing according to investigator's judgment (10 mg, 20 mg, or 40 mg a day of pitolisant; 100 mg, 200 mg or 400 mg a day of modafinil) followed by 5 weeks of stable dosing. Patients took four tablets a day in a double-dummy design to ensure masking. For the primary analysis, assessed in the intention-to-treat population, we assessed the superiority of pitolisant versus placebo, and the non-inferiority of pitolisant versus modafinil. This trial is registered with ClinicalTrials.gov, number NCT01067222.
  
  
  RESULTS
  Between May 26, 2009, and June 30, 2010, we screened 110 patients, 95 of whom were eligible and randomly assigned to treatment: 30 to placebo, 32 to pitolisant, and 33 to modafinil. Over the 8-week treatment period, mean ESS score reductions were -3·4 (SD 4·2) in the placebo group, -5·8 (6·2) in the pitolisant group, and -6·9 (6·2) in the modafinil group. Our primary analysis of between-group differences in mean ESS score at endpoint (adjusted for baseline) showed pitolisant to be superior to placebo (difference -3·0, 95% CI -5·6 to -0·4; p=0·024), but not non-inferior to modafinil (difference 0·12, 95% CI -2·5 to 2·7; p=0·250). We recorded 22 adverse events with pitolisant, 26 with modafinil, and ten with placebo. Six severe adverse events were treatment-related: one with pitolisant (abdominal discomfort) and five with modafinil (abdominal pain, abnormal behaviour, amphetamine-like withdrawal symptoms, lymphoadenopathy, and inner ear disorders).
  
  
  CONCLUSIONS
  Pitolisant at doses up to 40 mg was efficacious on EDS compared with placebo and well tolerated compared with modafinil. If these findings are substantiated in further studies, pitolisant could offer a new treatment option for patients with narcolepsy.
  
  
  BACKGROUND
  Bioprojet, France.
authors.affiliation: Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, University of Montpellier 1, Montpellier, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Dauvilliers
authors.forename: Claudio
authors.initials: C
authors.lastname: Bassetti
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Lammers
authors.forename: Isabelle
authors.initials: I
authors.lastname: Arnulf
authors.forename: Geert
authors.initials: G
authors.lastname: Mayer
authors.forename: Andrea
authors.initials: A
authors.lastname: Rodenbeck
authors.forename: Philippe
authors.initials: P
authors.lastname: Lehert
authors.forename: Claire-Li
authors.initials: CL
authors.lastname: Ding
authors.forename: Jeanne-Marie
authors.initials: JM
authors.lastname: Lecomte
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D017442:Histamine Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D009290:Narcolepsy / Q000188:drug therapy*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010919:Placebos; D012720:Severity of Illness Index; D016896:Treatment Outcome; D064690:Wakefulness-Promoting Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D017442:Histamine Agonists; D010880:Piperidines; D010919:Placebos; D064690:Wakefulness-Promoting Agents; C516975:pitolisant; D000077408:Modafinil